Cancer is the second leading cause of death in the United States, exceeded only by cardiovascular disease. (Cancer Facts and Figures 2005, American Cancer Society, Inc.) Despite recent advances in cancer diagnosis and treatment, surgery and radiotherapy may be curative if a cancer is found early, but current drug therapies for metastatic disease are by and large only palliative and seldom offer a long-term cure. Even with new chemotherapies entering the market, the need continues for effective new drugs used either in monotherapy or in combination with existing agents as first line therapy, and as second and third line therapies in treatment of resistant tumors.
Improving the specificity of agents used to treat cancer is of considerable interest because of the therapeutic benefits which would be realized if the side effects associated with the administration of these agents could be reduced. One approach for cancer treatment is targeting mitotic processes of mammalian cells. Examples of the therapeutic agents targeting mitosis include the taxanes, and the camptothecin class of topoisomerase I inhibitors.
An emerging target class for cancer treatment is mitotic kinesins. Mitotic kinesins are enzymes essential for assembly and function of the mitotic spindle, but are not generally part of other microtubule structures, such as in nerve processes. Mitotic kinesins play an essential role during all phases of mitosis. These enzymes are “molecular motors” that transform energy released by hydrolysis of ATP into mechanical force which drives the directional movement of cellular cargoes along microtubules. The catalytic domain sufficient for this task is a compact structure of approximately 340 amino acids. During mitosis, kinesins organize microtubules into the bipolar structure that is the mitotic spindle. Kinesins mediate movement of chromosomes along spindle microtubules, as well as structural changes in the mitotic spindle associated with specific phases of mitosis. Experimental perturbation of mitotic kinesin function causes malformation or dysfunction of the mitotic spindle, frequently resulting in cell cycle arrest and cell death.
Among the mitotic kinesins which have been identified is KSP (also termed Eg5). KSP belongs to an evolutionarily conserved kinesin subfamily of plus-end-directed microtubule motors that assemble into bipolar homotetramers consisting of antiparallel homodimers. During mitosis KSP associates with microtubules of the mitotic spindle. Microinjection of antibodies directed against KSP into human cells prevents spindle pole separation during prometaphase, giving rise to monopolar spindles and causing mitotic arrest and induction of programmed cell death. KSP and related kinesins in non-human organisms bundle antiparallel microtubules and slide them relative to one another, thus forcing the two spindle poles apart. KSP may also mediate anaphase B spindle elongation and focusing of microtubules at the spindle pole.
Human KSP (also termed HsEg5) has been described [Blangy, et al., Cell, 83:1159-69 (1995); Whitehead, et al., Arthritis Rheum., 39:1635-42 (1996); Galgio et al., J. Cell Biol., 135:339-414 (1996); Blangy, et al., J. Biol. Chem., 272:19418-24 (1997); Blangy, et al., Cell Motil Cytoskeleton, 40:174-82 (1998); Whitehead and Rattner, J. Cell Sci., 111:2551-61 (1998); Kaiser, et al., JBC 274:18925-31 (1999); GenBank accession numbers: X85137, NM004423 and U37426], and a fragment of the KSP gene (TRIP5) has been described [Lee, et al., Mol. Endocrinol., 9:243-54 (1995); GenBank accession number L40372]. Xenopus KSP homologs (Eg5), as well as Drosophila K-LP61 F/KRP 130 have been reported.
Certain quinazolinones have been recently described as being inhibitors of KSP [PCT Publ. WO 01/30768, May 3, 2001; PCT Publ. WO 01/98278, Dec. 27, 2001; PCT Publ. WO 01/30768, May 3, 2001; PCT Publ. WO 03/039460, May 15, 2003; PCT Publ. WO 03/043995, May 30, 2003; PCT Publ. WO 03/070701, Aug. 28, 2003; PCT Publ. WO 03/097053, Nov. 27, 2003; and PCT Publ. WO 04/009036, Jan. 29, 2004].
Quinazolinone derivatives are privileged structures present in many biologically active compounds such methaqualone, a sedative-hypnotic agent, chloroqualone, an antitussive agent, and piriqualone, an anticonvulsant. It has been known that quinazolinones and derivatives have a wide variety of biological properties such as hypnotic, analgesic, anticonvulsant, antitussive and anti-inflammatory activities.
Quinazolinone derivatives for which specific biological uses have been described include U.S. Pat. No. 5,147,875 describing 2-(substituted phenyl)-4-oxoquinazolines with bronchodilator activity is described. U.S. Pat. Nos. 3,723,432, 3,740,442, and 3,925,548 describe a class of 1-substituted-4-aryl-2(1H)-quinazolinone derivatives useful as anti-inflammatory agents. European patent publication EP 0 056 637 B1 claims a class of 4(3H)-quinazolinone derivatives for treating hypertension. European patent publication EP 0 884 319 A1 describes pharmaceutical compositions of quinazolin-4-one derivatives used for the treatment of neurodegenerative, psychotropic, and drug and alcohol induced central and peripheral nervous system disorders.
Quinazolinone derivatives are one of a growing list of therapeutic agents used for the treatment of cellular proliferate disorders, including cancer. In this area, for example, PCT WO 96/06616 describes a pharmaceutical composition containing a quinazolinone derivative to inhibit vascular smooth cell proliferation. PCT WO 96/19224 uses this same quinazolinone derivative to inhibit mesangial cell proliferation. U.S. Pat. Nos. 4,981,856, 5,081,124, and 5,280,027 describes the use of quinazolinone derivatives to inhibit thymidylate synthase, the enzyme that catalyzes the methylation of deoxyuridine monophosphate to produce thymidine monophosphate which is required for DNA synthesis. U.S. Pat. Nos. 5,747,498 and 5,773,476 describes quinazolinone derivatives used for the treatment of cancer characterized by over-activity or inappropriate activity of tyrosine receptor kinase. U.S. Pat. No. 5,037,829 claims (1H-azol-1-ylmethyl) substituted quinazoline compositions for the treatment of carcinomas that occur in epithelial cells. PCT WO 98/34613 describes a composition containing a quinazolinone derivative useful for attenuating neovascularization and for treating malignancies. U.S. Pat. No. 5,187,167 describes pharmaceutical compositions comprising quinazolin-4-one derivatives that possess anti-tumor activity.
The references cited herein are not admitted to be prior art to the claimed invention.